Delivery devices for administering a beneficial agent to a biological fluid environment of use are known in the prior art. Representative examples of various types of delivery devices are disclosed in European publications EP 25,699 and 164,241 and in U.S. Pat. Nos. 3,995,632, 4,111,202, 4,251,506, 4,612,008, 4,824,675, 4,865,598, 4,872,873, 4,876,093, 4,892,778, 4,915,949, 4,940,465 and 5,023,088.
While the prior art delivery devices usually work successfully for their intended purpose, the present inventors have observed that the devices do not function well when the formulation dispensed is a hydrophilic beneficial agent formulation; that is, a beneficial agent formulation where the agent is combined with a hydrophilic carrier. When a hydrophilic agent formulation is dispensed from the previous devices, uncontrolled release of the agent is often a problem, causing delivery of the agent into the environment of use in amounts and over periods of time that are not intended by the design of the device, and resulting in erratic or incorrect dosage profiles. This has been found to be particularly true in dynamic or vigorous environments such as active, grazing animals. Such uncontrolled release of a hydrophilic formulation has not been recognized or addressed in the prior art. The discrepancy between in vivo tests on animals under field conditions versus in vitro tests and in vivo tests on isolated animals was unexpected and surprising and could adversely affect the commercialization of the delivery devices.
One group of beneficial agents are the ionophores. Ionophores, or ion-bearers, as reported in Ann. N.Y. Acad. Sci., Vol. 264, pp 373-86 (1985), are polyether antibiotics that modulate the physiological transport of ions across biological membranes and alter the characteristics of fermentation in the animal, resulting in favorable metabolic changes. These valuable properties of ionophores led to their use as feed additives by the livestock industry. For example, the ionophores, when fed to ruminants, resulted in an improved feed-gain ratio, as reported in Feedstuffs, pp 14, 15 and 22 (1989). In one accepted use, ionophores are fed to feedlot cattle in confinement for improved feed efficiency. In this use, the ionophore first is mixed with a finely ground nonmedicated feedstuff to produce a premix, which premix is added to an air-dry feed for feeding to cattle, including steers and heifers.
While the above described prior art use of ionophores results in improved feed efficiency, usually of from 5 to 8 percent or higher, for steers and heifers, as reported in Feedstuffs (supra), serious shortcomings accompany this use. For example, since the ionophore is mixed with feed, one shortcoming is the difficulty to ascertain the amount of ionophore ingested by the animal because of feedlot losses such as spillage and scatter. Another shortcoming resides in the absence of controlled administration of known amounts of the ionophore over time, as the composition of the feed charged with the ionophore can vary with feed millers. Also, ionophores are sensitive to moisture in the environment, which moisture can adversely affect their usefulness, and the handling and transport of feeds containing ionophores can result in the segregation of particles carrying ionophores and change the concentration level to which cattle are exposed when fed over time. Then, since ionophores usually are mixed with feeds daily, this requires extra labor that adds to the cost of the ionophore-feedstuff.
In the light of the above presentation, it will be appreciated by those versed in the dispensing art to which this invention pertains that a pressing need exists for a dosage form that can deliver a beneficial agent, such as the ionophores, to a biological environment of use. The pressing need exists also for a dosage form that can store a beneficial agent in a hydrophilic carrier and deliver the beneficial agent and carrier at a controlled rate in a substantially constant dose per unit time over a prolonged period of time essentially independent of the environment of use. Such beneficial agent can be an ionophore and the environment of use can pertain to livestock that are confined and to livestock in the pasture. It will be appreciated further by those versed in the dispensing art that if such a novel and unique dosage form is provided that can administer a beneficial agent in a hydrophilic carrier in a rate-controlled dose over time and, simultaneously, provide the beneficial effects, the dosage form would represent an advancement and valuable contribution in the agent dosage form art.